The long-term goals of the "Genomics of AML" PPG are to define the genetic changes responsible for the development of acute myeloid leukemia in order to create improved molecular tools for diagnosis and disease stratification, and to identify new candidate genes for targeted therapeutic approaches. We intend to identify somatic mutations that are responsible for the initiation and progression of disease (Projects 1, 2, and 4 and Core C), and the genetic changes associated with relapse and chemotherapeutic resistance (Project 3). We also intend to identify mechanisms leading to increased AML susceptibility in patients who have received alkylator therapy (Project 5). To accomplish these aims, pathologic material and clinical data from AML patients is collected in Core A, and patient samples are banked and subjected to array-based genomic screens in Core B. To discover all of the mutations in AML genomes in an unbiased fashion, we proposed to sequence the entire genomes of the AML cells and normal skin cells from 10 individuals with FAB M1 AML at the renewal of the grant (Project 1). We have now accomplished this goal for 1 case (Nature 456:66-72, 2008), and will finish a second and third M1 AML genome during year 1 of the grant cycle. Because of remarkable improvements in the cost and quality of DNA sequence obtained with 'next generation'sequencing platforms, we request $900,000 (300K/year) in supplemental funds in years 2-4 to further accelerate the work in Project 1. If supplemental funds are granted, we will sequence 7 new cytogenetically normal AML M1 genomes in year 2. In year 3, we will be able to sequence 10 total M3 AML genomes bearing t(15;17) as the sole cytogenetic abnormality. Since the PML-RARA fusion protein caused by this translocation is known to initiate M3 AML, we will be able to contrast the kinds of mutations found in these two very distinct, very well defined AML subtypes. The AML genomes selected for year 4 will be directed by the results of years 2 and 3, and could potentially involve dozens of additional carefully selected cases if costs continue to fall. All of the DNA samples required for the study are currently available and consented for whole genome sequencing.